Abstract Hyperoxaluria is a major risk factor in the development of calcium oxalate kidney stone disease which presently occurs in about 12% of the American population, costing an estimated $2 billion annually. Despite the significant and serious clinical consequences of hyperoxaluria, which can be associated with numerous diseases and conditions, including an emerging population of patients who undergo gastric bypass surgery, there is still no effective pharmacological treatment to resolve this problem. Consequently, patients have to resort to invasive procedures to eliminate kidney stones and/or suffer the ramifications, including the possibility of renal failure and even death. Several key pieces of information obtained from our studies over the years have supported the notion that a significant amount of the body burden of oxalate can be eliminated through the intestinal tract resulting in reduced amounts of oxalate passing through the kidneys. This basic proof of principle was demonstrated earlier in rats with chronic renal failure where urinary oxalate was reduced 50 % due to the induction of enteric oxalate elimination. In addition, we demonstrated that a mouse model with elevated concentrations of oxalate in the blood and urine, due to the genetic disease of Primary Hyperoxaluria, type 1, were normalized by enteric oxalate excretion being initiated in the presence of the probiotic bacterium, Oxalobacter sp. Hence, there exists considerable interest in exploiting the intestine as a means of alleviating the systemic oxalate load to mitigate the risk of stone formation and the eventual consequences of this kidney disease. The investment in furthering this beneficial approach involves a more in-depth look at the pathways oxalate utilizes to cross the intestinal barrier, and specifically, how they are regulated. While we have been steadily developing an understanding about the proteins involved, which belong to the Slc26 gene family, we cannot currently explain how these transporters are regulated in the different segments of the intestine. Based upon some very provocative preliminary data, we have established a research plan with two comprehensive, integrated Specific Aims The strength of this research strategy comprises a number of innovative approaches coupled with a solid, feasible experimental design in a concerted effort to determine two major ?unknowns?; (i) how the components of the bicarbonate-buffering system (pH, CO2 and HCO3- in conjunction with carbonic anhydrase), and (ii) how the cAMP-dependent regulatory pathways modulate net oxalate secretion and the enteric elimination of oxalate. This knowledge will represent a crucial step toward realizing the therapeutic potential of the intestine for resolving hyperoxaluria. 1